NAFLD lacks accurate and robust non-invasive biomarkers to grade and stage histologic disease activity. This is a critical barrier to understanding the influence of this important environmental risk factor (increased/habitual fructose consumption) on the pathogenesis and progression of NAFLD. Currently, reliable assessment NAFLD requires liver biopsy and interpretation of histology. Serum aminotransferase levels and conventional imaging methods can detect liver fat but cannot grade or stage NAFLD. Furthermore, current developments in biomarker are cross-sectional in nature and do not characterize the dynamic changes which underlie liver injury in patients with NAFLD. In vivo 31P MRS permits the evaluation of dynamic changes of individual phosphorus-containing metabolites in the liver parenchyma, such as phosphomonoester (PME), ATP, and inorganic phosphate (Pi). Intravenous fructose load alters phosphorus metabolites and allows assessment of liver function by 31P MRS. Other investigators have demonstrated that fructose loading could be used effectively as a tool to investigate change in metabolic steps of hepatic metabolism in humans with alcohol-related liver disease. Further, IV fructose loading causes significantly higher ATP degradation and uric acid production in cirrhotic patients than in healthy controls. The associations between fructose, increased uric acid, and hepatic ATP depletion has been previously described. Increased uric acid is an independent risk factor for NAFLD and in keeping with our hypothesis, hyperuricemia may be a surrogate marker of impaired hepatic energy homeostasis in patients with NAFLD. The proposed mechanism for fructose-related hepatic ATP depletion, NAFLD, NASH and the associated hyperuricemia is depicted in Figure 1 is novel, innovative, scientifically rigorous and address an important public health concern—the impact of fructose on the rising epidemic of NAFLD.